First-pass metabolism of midazolam by the human intestine.

The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and 1'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 +/- 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 +/- 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates.

A comparison of thromboelastography with heparinase or protamine sulfate added in vitro during heparinized cardiopulmonary bypass.

Thromboelastography (TEG) has been used after cardiopulmonary bypass (CPB) to diagnose excessive postoperative hemorrhage. Conventional TEG during CPB is not possible due to the sensitivity of the TEG to even small amounts of heparin, which produces a nondiagnostic tracing. The purpose of this study was to compare heparin neutralization using heparinase or protamine in TEG blood samples obtained during CPB. TEG testing was performed on 48 patients before, during and after CPB. Tissue plasminogen activator activity and antigen were measured on a subset of 32 patients. We found: 1) heparinase neutralized at least 10 IU/ml heparin while 1.6 ug/ml protamine neutralized up to 7 IU/ml heparin, 2) in samples with complete heparin neutralization by both methods, there was no significant difference in the R values, 3) while there was good correlation for other TEG parameters between heparinase and protamine treated samples, heparinase treatment produced shorter K values and higher angle, MA and A60, 4) while fibrinolysis was detected using both methods, heparinase treatment suppressed fibrinolysis in the TEG in both samples from patients and after in vitro addition of tissue plasminogen activator, 5) TEG was not a sensitive indicator of t-PA activity, detecting only 21% of samples with increased t-PA activity during bypass, and 5) heparinase was at least 100 times more expensive than protamine. We conclude that while both heparinase and protamine can be used to neutralize heparin in TEG samples obtained during CPB, protamine neutralization is more sensitive to fibrinolysis and less expensive, but the protamine dose must be carefully selected to match the heparin level used at individual institutions.

Thromboelastography and liver transplantation.

TEG has played an integral part in the growth of liver transplantation. The group at the University of Pittsburgh early on realized that coagulation dysfunction during liver transplantation would be both severe and dynamic. Each phase of the operation appears to have both predictable and unexpected changes in clot dynamics. The routine coagulation profile, although of great use, does not provide an overview of the interaction of stimulators, inhibitors, and available procoagulants to effect a final process, the production of a solid clot. The TEG is a unique gross test of clot strength perfectly suited to the changes during liver transplantation. The initial pioneering work during liver transplantation has inspired the work of others in related surgical fields to explore its utility. There is little doubt that its full utility has not yet been realized. Many questions still remain with regard to liver transplantation. New medications such as aprotinin will be applied to this procedure over the next few years. What effect these new medications will have on hemorrhage or thrombosis of vascular anastomoses is yet to be adequately explored. A new awareness appears to be arriving that normal or excessively hypercoagulable states could contribute to such thromboses. TEG as a technology will certainly contribute to a number of future studies and clinical care, which will enhance the conduct of liver transplantation in the future.

Failure rate of pulse oximetry in the postanesthesia care unit.

OBJECTIVE: The objective of this study was to prospectively examine the incidence of patient-related failure of pulse oximetry in the postanesthesia care unit (PACU). METHODS: We studied 2,937 patients who, after receiving anesthesia, were admitted to the PACU at the University of Washington Medical Center from December 1989 through May 1990. Pulse oximetry readings were recorded using a Nellcor N-200 oximeter without electrocardiographic synchronization. Failure was defined as the inability to obtain a pulse oximetry reading for 2 or more 15-minute periods after eliminating probe position or mechanical malfunctions. RESULTS: The overall failure rate in our study was 0.64%, with 19 patient-related pulse oximetry failures from 2,937 cases. Patients on whom the device failed were significantly older (62 +/- 18 vs 46 +/- 19 yr [mean +/- SD]; p < 0.01), had higher median American Society of Anesthesiologists status (3 vs 2), and had longer operations than nonfailure patients (328 +/- 182 vs 185 +/- 127 min; p < 0.01). There was no difference in the duration of PACU times for both groups. CONCLUSIONS: The failure rate and patient characteristics compare favorably with a previously published study of intraoperative pulse oximetry failure. We conclude that while the pulse oximeter is a reliable instrument for the measurement of blood oxygenation, there is a small but consistent incidence of patient-related failure with this monitoring device in the PACU.

Substitution reactions of a water-soluble metalloporphyrin with azide and 1,1,3,3-tetramethyl-2-thiourea.

The substitution reactions of tetrakis-(4-N-methylpyridyl)porphinecobalt (III) (CoIIITMpyP) with azide and with 1,1,3,3-tetramethyl-2-thiourea (TMTU) have been studied as a function of pH at 25 degrees and an ionic strength of 0.5 M. The mechanistic pathway proposed for thiocyanate [1] and pyridine [2] is applicable to these ligands as well once allowance is made for two attacking forms of azide, N3- and HN3. A TMTU axial substituent has about the same influence on the rate of further ligand substitution as does SCN- and a much larger influence than does azide. Similar behavior between bound SCN- and bound TMTU is also shown in electron-transfer reactions with Ru(NH3)62+. Whereas both sulfur-containing ligands enhance the rate relative to the diaquo complex, the azide complex undergoes reduction an order of magnitude more slowly than does the diaquo complex.

Changes in transfusion therapy and reexploration rate after institution of a blood management program in cardiac surgical patients.

A retrospective study was performed to determine the impact of a coagulation and transfusion management program on blood utilization in 1,079 sequential patients for myocardial revascularization and open ventricle or combined procedures. Four hundred and eighty-eight patients (group 1) before, and 591 patients (group 2) after institution of thromboelastography (TEG)-guided coagulation were studied and compared for transfusion requirements, donor exposure, and the incidence of reoperation for hemorrhage. Group 2 patients had a significantly lower incidence of overall transfusion (78.5% v 86.3%) during hospitalization and in total transfusion in the operating room (57.9% v 66.4%). The incidence of each transfusion subtype was also significantly lower in group 2 patients. Actual total median donor exposure was 8 in group 1 patients and 6 exposures in group 2 patients. Mediastinal reexploration for hemorrhage was 5.7% before institution of TEG-based coagulation monitoring and 1.5% in TEG-monitored patients. Use of TEG monitoring before reexploration has decreased the cost and potential risk for patients undergoing CABG surgery.

Spinal cord compression following labor and delivery with epidural analgesia.

Transient back pain is not uncommon during pregnancy and the postpartum period. Following an epidural anesthetic, back pain persisted in a postpartum patient beyond the expected period of soreness. Further diagnostic evaluation led to diagnosis and surgical decompression of a herniated thoracic disc.